EP2108366A1 - Chinonderivat-2,3-Dimethoxy-5-Methyl-6-(10-Hydroxydecyl)-1,4-Benzochinon zur Behandlung von durch muskuläre Dystrophie vermittelten Atemwegserkrankungen - Google Patents

Chinonderivat-2,3-Dimethoxy-5-Methyl-6-(10-Hydroxydecyl)-1,4-Benzochinon zur Behandlung von durch muskuläre Dystrophie vermittelten Atemwegserkrankungen Download PDF

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Publication number
EP2108366A1
EP2108366A1 EP08007069A EP08007069A EP2108366A1 EP 2108366 A1 EP2108366 A1 EP 2108366A1 EP 08007069 A EP08007069 A EP 08007069A EP 08007069 A EP08007069 A EP 08007069A EP 2108366 A1 EP2108366 A1 EP 2108366A1
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EP
European Patent Office
Prior art keywords
idebenone
muscular dystrophy
treatment
dmd
respiratory
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP08007069A
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English (en)
French (fr)
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EP2108366B1 (de
Inventor
Gunnar Buyse
Thomas Meier
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Santhera Pharmaceuticals Schweiz GmbH
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Santhera Pharmaceuticals Schweiz GmbH
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Application filed by Santhera Pharmaceuticals Schweiz GmbH filed Critical Santhera Pharmaceuticals Schweiz GmbH
Priority to ES08007069T priority Critical patent/ES2370607T3/es
Priority to AT08007069T priority patent/ATE529104T1/de
Priority to SI200830477T priority patent/SI2108366T1/sl
Priority to EP08007069A priority patent/EP2108366B1/de
Priority to DK08007069.1T priority patent/DK2108366T3/da
Priority to PT08007069T priority patent/PT2108366E/pt
Priority to PL08007069T priority patent/PL2108366T3/pl
Priority to JP2011503366A priority patent/JP2011516513A/ja
Priority to US12/934,089 priority patent/US20110092469A1/en
Priority to MX2010011099A priority patent/MX2010011099A/es
Priority to AU2009235681A priority patent/AU2009235681B2/en
Priority to NZ588181A priority patent/NZ588181A/en
Priority to PCT/EP2009/002478 priority patent/WO2009124693A1/en
Priority to CA2719440A priority patent/CA2719440C/en
Publication of EP2108366A1 publication Critical patent/EP2108366A1/de
Priority to ZA2010/06905A priority patent/ZA201006905B/en
Publication of EP2108366B1 publication Critical patent/EP2108366B1/de
Application granted granted Critical
Priority to HR20110813T priority patent/HRP20110813T1/hr
Priority to CY20121100068T priority patent/CY1112313T1/el
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone) for treating and/or preventing respiratory illness associated with certain forms of muscular dystrophy.
  • Duchenne muscular dystrophy is a recessively inherited progressive form of muscle-wasting disease affecting ⁇ 1 in 3'000 boys. The reported incidence is 25/100,000 live male births worldwide. First signs of the disease become apparent when boys start to walk. Muscle wasting occurs initially in proximal and later in distal muscle groups leading to the loss of ambulation in teenage patients. Mutations in the dystrophin gene and absence of dystrophin protein ultimately lead to death of DMD patients at early adulthood, mainly because of respiratory or cardiac failures. Clinical measures to improve quality of life comprise orthopedic surgery and nighttime ventilation.
  • Becker muscular dystrophy is caused by different mutations of the same dystrophin gene but has a milder clinical course and the patients have a prolonged life expectancy when compared to DMD patients.
  • Cellular processes underlying DMD-associated muscle wasting include the loss of skeletal muscle fibers and accompanying invasion by connective and adipose tissue. Progressive weakness of the skeletal musculature, cardiac involvement and respiratory insufficiency leads to early morbidity and mortality in DMD/BMD patients.
  • Both DMD and BMD are caused by mutations in the dystrophin gene.
  • the dystrophin gene consists of 2700 kbp and is located on the X chromosome (Xp21.2, gene bank accession number: M18533).
  • the 14 kbp long mRNA transcript is expressed predominantly in skeletal, cardiac and smooth muscle and to a limited extent in the brain.
  • the mature dystrophin protein has a molecular weight of ⁇ 427 kDa and belongs to the spectrin superfamily of proteins ( Brown S.C., Lucy J.A. (eds), "Dystrophin", Cambridge University Press, 1997 ). While the underlying mutation in DMD leads to a lack of dystrophin protein, the milder BMD-phenotype is a consequence of mutations leading to the expression of abnormal, often truncated, forms of the protein with residual functionality.
  • dystrophin serves as a molecular linker between the cytoskeleton and the muscle cell membrane and, indirectly, via the so-called dystrophin-associated protein complex (DAPC) also to the extracellular matrix.
  • DAPC dystrophin-associated protein complex
  • Known binding partners of dystrophin also include syntrophin, dystrobrevin, the neuronal type nitric oxide synthase (nNOS) and the sarcoglycan-sarcospan (SS) complex.
  • Dystrophin is also important for the assembly or integrity of the DAPC-complex itself, as it has been shown that in dystrophin-deficient muscle cells of DMD patients many components of the DAPC complex are reduced or absent in the sarcolemma. Absence of functional dystrophin protein leads to disruption of the mechanical link between actin cytoskeleton and the muscle cell sarcolemma which in turn leads to deterioration of myotubes and muscle weakness ( Brown S.C., Lucy J.A. (eds), "Dystrophin", Cambridge University Press, 1997 ).
  • Respiratory insufficiency associated with DMD and BMD is currently treated only symptomatically or supportive by airway clearance, respiratory muscle training, non-invasive nocturnal ventilation, daytime non-invasive ventilation and continuous invasive ventilation as recommended by the American Thoracic Society. Spinal surgery in combination with nocturnal ventilation improves median survival to 30 years.
  • the present invention relates to idebenone (2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone) for the prophylaxis and/or treatment of respiratory illness (respiratory weakness andor insufficiency) in a muscular dystrophy, in particular Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD).
  • DMD Duchenne Muscular Dystrophy
  • BMD Becker Muscular Dystrophy
  • Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), the vital cell membrane antioxidant and essential constituent of the adenosine-triphosphate (ATP)-producing mitochondrial electron transport chain (ETC). Idebenone has the ability to operate under low oxygen tension situations. Due to its ability to inhibit lipid peroxidation, idebenone protects cell membranes and mitochondria from oxidative damage ( Zs.-Nagy I (1990) Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review. Arch. Gerontol. Geriatr. 11:177-186 ). It's antioxidant properties protect against cerebral ischemia and nerve damage in the central nervous system.
  • CoQ10 coenzyme Q10
  • ATP adenosine-triphosphate
  • ETC mitochondrial electron transport chain
  • Idebenone also interacts with the ETC, preserving ATP formation in ischemic states. This compound is already used as a nootropic drug and has also been shown to stimulate nerve growth factor, a characteristic that could be important in the treatment of Alzheimer's and other neurodegenerative diseases. Idebenone is described in the specification of Japanese Patent Examined Publication No. 3134/1987 filed by Takeda Chemical Industries, Ltd. In addition it has been shown that idebenone can be applied in the treatment of diseases associated with iron overload, particularly Friedreich Ataxia ( US Patent 6,133,322 ).
  • Idebenone has the following formula:
  • Idebenone is preferably administered in dosage ranges form 5 mg/kg/day to 60mg/kg/day, more preferably in a dosage range of 5 mg/kg/day to 40 mg/kg/day and most preferred in a dosage range of 10 mg/kg/day to 30 mg/kg/day.
  • the idebenone is preferably administered at least one, preferably more times a day, preferably for at least 3 months, more preferably for at least 6 months, most preferably for 6 months to 12 months to observe the initial amelioration of muscle force and improved heart function and normalized heart anatomy.
  • the preferred treatment is lifelong.
  • Preferred modes of administration are oral, i.p., i.v., i.m., i.c, parenteral, intranasal, transdermal and oromucosal, whereas the oral and oromucosal administrations are the most preferred modes of administration.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of idebenone.
  • Further modes of administration include rectal, topical, ocular, pulmonary or nasal administration.
  • the dosage forms include, e.g., tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments and aerosols, whereas tablets are preferred.
  • kits defined as fast disintegrating oral film form products for the delivery of idebenone, or orally disintegrating tablets (ODTs) containing idebenone.
  • the effective dosage of the active ingredient employed may vary depending on the particular compounds employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art, a preferred dosage having been mentioned above.
  • Idebenone as used in the context of the present invention is preferably formulated into a dosage form prior to administration. Accordingly, the idebenone may be combined with any suitable pharmaceutical carrier.
  • the pharmaceutical preparations for use in accordance with the present invention may be prepared by normal procedures using well-known and readily available ingredients. In making the formulations, idebenone is usually mixed with a carrier, or diluted by a carrier, or enclosed with a carrier, which may be in the form of a capsule, cachet, paper or other container.
  • the carrier When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material, which acts as a vehicle, excipient or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, orally disintegrating tablets and oral wafers.
  • Suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents and/or flavoring agents.
  • the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • Idebenone is toxically safe which means that it can be used as a pharmaceutical active agent in a medicament.
  • Idebenone can be combined with excipients, fillers, solvents, diluents, dyes and/or binders.
  • auxiliary substances as well as the amounts thereof to be used depends on whether the medicinal drug is to be administered orally, via the oral mucosa, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically.
  • suitable preparations are in the form of tablets, sugar-coated pills, capsules, granular powders, drops, juices and syrups, while for parenteral, topical and inhalative application suitable forms are solutions, suspensions, easily reconstitutable dry preparations as well as sprays.
  • the Idebenone can be administered in a sustained-release substance, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, and are suitable as percutaneous application preparations. Forms of preparations that can be used orally or percutaneously may produce a delayed release of the compounds. Idebenone formulations are e.g. described in several patents, for example in WO 99/07355 , JP11116470 and WO 2008/019769 .
  • Preferred formulations for use in accordance with the present invention contain 45 mg, 60 mg or 150 mg of Idebenone in a film-coated tablet containing lactose, cellulose, croscarmellose sodium, PVP (Plasdone® K25), magnesium stearate veg. and colloidal silicon dioxide.
  • idebenone-containing wafers defined as fast disintegrating oral film form products for the delivery of idebenone or orally disintegrating tablet (ODT) containing idebenone.
  • Idebenone may be administered in combination with a second therapeutic agent, wherein said second therapeutic agent is preferably selected from glucocorticosteroids such as 6a-methylprednisolone-21 sodium succinate (solumedrol®) or deflazacort (calcort®) which are routinely used in DMD patients for treatment of inflammation and muscle weakness.
  • glucocorticosteroids such as 6a-methylprednisolone-21 sodium succinate (solumedrol®) or deflazacort (calcort®) which are routinely used in DMD patients for treatment of inflammation and muscle weakness.
  • idebenone may be administered in combination with any medication used in DMD patients to treat DMD-associated cardiomyopathy such as ACE-inhibitors, beta-blockers and diuretics.
  • Idebenone and the further active agent can be used simultaneously, separately or sequentially in order to treat or prevent the disease symptoms.
  • the two active agents may be provided in a single dosage form or a separate formulation, each formulation containing at least one of the two active agents.
  • Efficacy of idebenone on respiratory parameters in Duchenne Muscular Dystrophy (DMD) patients was assessed in a double-blind, placebo-controlled, randomised parallel group, clinical trial conducted in one singe clinical center.
  • DMD patients at age 8 to 16 years were treated with idebenone or placebo over a period of 52 weeks.
  • patients who met the protocol eligibility criteria were enrolled at the study centre and randomised to daily treatment of idebenone (150 mg, 3x daily; total daily dose of 450 mg) or placebo (3x daily).
  • Efficacy was assessed at baseline and at weeks 26 and 52.
  • the inclusion and exclusion criteria were assessed at Screening and confirmed at Visit 1 (baseline visit), prior to first administration of study medication. The following inclusion and exclusion criteria were used to decide on the eligibility for a patient to become enrolled into the study.
  • Idebenone was formulated as a round biconvex shaped, film-coated orange tablet, with a 10 mm diameter, containing 150 mg of idebenone and Lactose Monohydrate, Microcrystalline Cellulose, Croscarmellose Sodium, Povidone (Plasdone® K25), Magnesium Stearate and Silicon Dioxide as excipients.
  • the tablet is manufactured by a wet granulation process performed with a high-shear granulator, followed by compression on a rotary tabletting machine and film-coating of the cores in a perforated pan coater.
  • the composition of the placebo is based on the composition of the 150 mg film-coated tablet.
  • Placebo tablets are manufactured by direct compression, followed by film-coating. Both idebenone (150 mg) and matching placebo were administered as an oral tablet. Patients were to take 1 tablet, 3 times a day with meals, for 12 months (52 weeks).
  • Pulmonary function testing was performed by one clinical evaluator (physical therapist) with longstanding expertise in the assessment of children with neuromuscular diseases, using state of the art equipment and methods. Testing was done with the patient sitting, with a standardized order of testing. Lung volumes (FVC, FEV1) were measured using a handheld Koko spirometer (PDS Instrumentation, Louisville, USA).
  • Pulmonary function testing included the following parameters:
  • MIP maximal inspiratory pressure
  • Efficacy of idebenone was determined for the parameters listed above as changes between baseline and end of treatment (at week 52) and comparisons were made between idebenone treated and placebo treated subjects.
  • the above described clinical testing allows the monitoring of any improvement on respiratory parameters in DMD patients as the result of the idebenone treatment.
  • Idebenone improves functional respiratory parameters in patients with DMD.
EP08007069A 2008-04-09 2008-04-09 Idebenon zur Behandlung von durch muskuläre Dystrophie vermittelten Atemwegserkrankungen Active EP2108366B1 (de)

Priority Applications (17)

Application Number Priority Date Filing Date Title
ES08007069T ES2370607T3 (es) 2008-04-09 2008-04-09 Idebenona para el tratamiento de enfermedad respiratoria en distrofia muscular.
AT08007069T ATE529104T1 (de) 2008-04-09 2008-04-09 Idebenon zur behandlung von durch muskuläre dystrophie vermittelten atemwegserkrankungen
SI200830477T SI2108366T1 (sl) 2008-04-09 2008-04-09 Idebenon za zdravljenje respiratorne bolezni pri miĺ iäśni distrofiji
EP08007069A EP2108366B1 (de) 2008-04-09 2008-04-09 Idebenon zur Behandlung von durch muskuläre Dystrophie vermittelten Atemwegserkrankungen
DK08007069.1T DK2108366T3 (da) 2008-04-09 2008-04-09 Idebenon til behandling af respiratorisk sygdom ved muskeldystrofi
PT08007069T PT2108366E (pt) 2008-04-09 2008-04-09 Derivado de quinona 2,3-dimetoxi-5-metil-6-(10- hidroxidecil)-1,4-benzoquinona para o tratamento de doença respiratória em distrofia muscular
PL08007069T PL2108366T3 (pl) 2008-04-09 2008-04-09 Idebenon stosowany w leczeniu chorób układu oddechowego towarzyszących dystrofii mięśniowej
AU2009235681A AU2009235681B2 (en) 2008-04-09 2009-04-03 Quinone derivative 2,3-dimethoxy-5- methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of respiratory illness in muscular dystrophy
US12/934,089 US20110092469A1 (en) 2008-04-09 2009-04-03 Quinone derivative 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of respiratory illness in muscular dystrophy
MX2010011099A MX2010011099A (es) 2008-04-09 2009-04-03 Derivado de quinona 2,3-dimetoxi-5-metil-6-(10-hidroxidecil)-1,4-b enzoquinona para el tratamiento de enfermedad respiratoria en distrofia muscular.
JP2011503366A JP2011516513A (ja) 2008-04-09 2009-04-03 筋ジストロフィーの呼吸器疾患を治療するためのキノン誘導体２，３−ジメトキシ−５−メチル−６−（１０−ヒドロキシデシル）−１，４−ベンゾキノン
NZ588181A NZ588181A (en) 2008-04-09 2009-04-03 Idebenone for the treatment of respiratory illness in muscular dystrophy
PCT/EP2009/002478 WO2009124693A1 (en) 2008-04-09 2009-04-03 Quinone derivative 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of respiratory illness in muscular dystrophy
CA2719440A CA2719440C (en) 2008-04-09 2009-04-03 Quinone derivative 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of respiratory illness in muscular dystrophy
ZA2010/06905A ZA201006905B (en) 2008-04-09 2010-09-28 Quinone derivative 2,3-dimerhoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of respiratory illness in muscular dystrophy
HR20110813T HRP20110813T1 (hr) 2008-04-09 2011-11-02 Idebenon za liječenje respiratornih bolesti u mišićnoj distrofiji
CY20121100068T CY1112313T1 (el) 2008-04-09 2012-01-18 Ιδεβενονη για τη θεραπεια της αναπνευστικης νοσου στη μυϊκη δυστροφια

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP08007069A EP2108366B1 (de) 2008-04-09 2008-04-09 Idebenon zur Behandlung von durch muskuläre Dystrophie vermittelten Atemwegserkrankungen

Publications (2)

Publication Number Publication Date
EP2108366A1 true EP2108366A1 (de) 2009-10-14
EP2108366B1 EP2108366B1 (de) 2011-10-19

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EP08007069A Active EP2108366B1 (de) 2008-04-09 2008-04-09 Idebenon zur Behandlung von durch muskuläre Dystrophie vermittelten Atemwegserkrankungen

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Country Link
US (1) US20110092469A1 (de)
EP (1) EP2108366B1 (de)
JP (1) JP2011516513A (de)
AT (1) ATE529104T1 (de)
AU (1) AU2009235681B2 (de)
CA (1) CA2719440C (de)
CY (1) CY1112313T1 (de)
DK (1) DK2108366T3 (de)
ES (1) ES2370607T3 (de)
HR (1) HRP20110813T1 (de)
MX (1) MX2010011099A (de)
NZ (1) NZ588181A (de)
PL (1) PL2108366T3 (de)
PT (1) PT2108366E (de)
SI (1) SI2108366T1 (de)
WO (1) WO2009124693A1 (de)
ZA (1) ZA201006905B (de)

Cited By (5)

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CN103040779A (zh) * 2013-01-01 2013-04-17 刘炜 用于神经系统疾病的口服固体药物组合物
WO2013107810A1 (en) * 2012-01-20 2013-07-25 Lts Lohmann Therapie-Systeme Ag Transmucosal administration system for a pharmaceutical drug
EP2620141A1 (de) * 2012-01-25 2013-07-31 Santhera Pharmaceuticals (Schweiz) AG Dünnfilm-Arzneimittelabgabesystem für die transmukosale Verabreichung eines Benzochinon-Derivates
WO2014035356A1 (en) * 2012-08-31 2014-03-06 Mahmut Bilgic Tablet formulations comprising a quinone derivative active agent
WO2022258629A1 (en) 2021-06-07 2022-12-15 Katholieke Universiteit Leuven Idebenone in the treatment of drug resistant epilepsy

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CN105307723A (zh) * 2013-03-15 2016-02-03 萨勒普塔医疗公司 改进的用于治疗肌营养不良的组合物
CN109364050B (zh) * 2018-10-19 2021-02-02 大连医科大学 艾地苯醌在制备治疗肺动脉高压药物中的应用

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WO2013107810A1 (en) * 2012-01-20 2013-07-25 Lts Lohmann Therapie-Systeme Ag Transmucosal administration system for a pharmaceutical drug
US10806703B2 (en) 2012-01-20 2020-10-20 Lts Lohmann Therapie-System Ag Transmucosal administration system for a pharmaceutical drug
US10716762B2 (en) 2012-01-20 2020-07-21 Lts Lohmann Therapie-Systeme Ag Transmucosal administration system for a pharmaceutical drug
EP3488846A1 (de) * 2012-01-20 2019-05-29 LTS Lohmann Therapie-Systeme AG System zur transmukosalen verabreichung für ein pharmazeutikum
CN104271123A (zh) * 2012-01-20 2015-01-07 Lts勒曼治疗系统股份公司 药物的经粘膜给药系统
CN104271123B (zh) * 2012-01-20 2018-09-25 Lts勒曼治疗系统股份公司 药物的经粘膜给药系统
WO2013110442A1 (en) * 2012-01-25 2013-08-01 Santhera Pharmaceuticals (Schweiz) Ag Thin film drug delivery system for the transmucosal administration of a 1,4- benzoquinone derivative
EP2620141A1 (de) * 2012-01-25 2013-07-31 Santhera Pharmaceuticals (Schweiz) AG Dünnfilm-Arzneimittelabgabesystem für die transmukosale Verabreichung eines Benzochinon-Derivates
WO2014035356A1 (en) * 2012-08-31 2014-03-06 Mahmut Bilgic Tablet formulations comprising a quinone derivative active agent
CN103040779B (zh) * 2013-01-01 2015-04-15 刘炜 用于神经系统疾病的口服固体药物组合物
CN103040779A (zh) * 2013-01-01 2013-04-17 刘炜 用于神经系统疾病的口服固体药物组合物
WO2022258629A1 (en) 2021-06-07 2022-12-15 Katholieke Universiteit Leuven Idebenone in the treatment of drug resistant epilepsy

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EP2108366B1 (de) 2011-10-19
JP2011516513A (ja) 2011-05-26
AU2009235681B2 (en) 2012-04-05
US20110092469A1 (en) 2011-04-21
PL2108366T3 (pl) 2012-03-30
MX2010011099A (es) 2010-11-01
HRP20110813T1 (hr) 2011-11-30
WO2009124693A1 (en) 2009-10-15
ZA201006905B (en) 2011-06-29
NZ588181A (en) 2011-11-25
DK2108366T3 (da) 2012-01-30
CA2719440C (en) 2013-07-16
ES2370607T3 (es) 2011-12-20
CY1112313T1 (el) 2015-12-09
SI2108366T1 (sl) 2012-01-31
AU2009235681A1 (en) 2009-10-15
CA2719440A1 (en) 2009-10-15
ATE529104T1 (de) 2011-11-15
PT2108366E (pt) 2011-11-10

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